Alzheimer's disease (AD) is the most common cause of dementia and the sixth leading cause of death in the United States. It is critical that we find new therapies to prevent and treat AD. The experiments in this proposal are designed to find new pathways by which toxic forms of beta amyloid (Aβ), a peptide associated with AD, damages microtubules, tube-like structures used to move components around in cells, including neurons in the brain. Typically, damage to microtubules is blamed on abnormal tau formations in the Alzheimer’s brain, but we plan to test the novel hypothesis that Aβ has neurodegenerative effects independent of tau that affect microtubule stability, and that microtubule stabilizing agents can protect neurons against Aβ neurotoxicity. New drugs will be tested to determine if they can reverse some of the detrimental effects of Aβ accumulation in the brain.

Atherosclerosis, or hardening of the arteries, is increasingly recognized as an important risk factor for dementia. Yet, it remains unclear whether the progression of atherosclerosis at different locations in the arterial system also contributes to changes in the structure or function of the brain, and ultimately to dementia. Knowledge of the dynamics of atherosclerosis and its role in brain changes will greatly improve our insight into the development of dementia. At a later point, this knowledge may even offer therapeutic or preventive opportunities to reduce the number of persons suffering from dementia by targeting atherosclerosis.

Numerous studies have suggested that vascular factors (blood supply) are involved in the development of glaucoma, but it is currently not known whether a reduction in blood supply to the eye is a cause or an effect of the glaucoma disease process. Recent advances in imaging technology have made it possible to visualize and measure the retinal blood supply, as well as assess the deep layers of the optic nerve head, including the lamina cribrosa, during routine eye exams. This prospective clinical research study will investigate whether changes in the retinal blood supply precede or follow other structural and mechanical changes in glaucoma.

Age-related macular degeneration (AMD) is one of the leading causes of blindness in the world but its genetics is still unclear. Most of the DNA variations in AMD patients are found outside of the genes, and it is extremely hard to know whether these variants are actual mutations and what genes they affect. We have found that some of these variants are located in genome regions conserved down to the zebrafish, and surrounded by the same neighborhood of genes as in the human genome. Their preservation in the zebrafish allows us to visualize in this transparent genetic vertebrate model whether these variants are just neutral or if they disrupt the regulation of one the neighbor genes, possibly revealing the actual gene affected in AMD human patients.

ID:

M2017209

Co-principal Investigators:

Romain Madelaine, PhD

Collaborators:

Jeffrey Goldberg, MD, PhD; Douglas Vollrath, MD, PhD

July 1, 2017 to June 30, 2019

Macular Degeneration

Standard

$160,000

This grant is made possible by support from the Nancy Ferguson Seeley Trust in memory of Mildred F. Ferguson.

Human genetic studies strongly point to apolipoprotein E (APOE) and microglia (the immune cells of the brain) as, respectively, the most important gene and cell type in the chain of events leading to Alzheimer’s disease(AD), a common disorder in the elderly in which the brain is damaged and memories falter. In normal conditions, microglial cells do not make APOE; however, in disease conditions, they sense the brain damage and respond by churning out APOE. It is unclear why this occurs. The goal of this project is to answer this question in a mouse model where the APOE gene is switched off in microglia.

A part of the immune system known as complement gets activated and is known to be an underlying cause of age-related macular degeneration (AMD) in a very significant portion of individuals. Although there are many animal models of AMD, there are almost none that exhibit disease similar to that in humans, specifically because of activation of the complement system. We recently developed such an animal model and propose to use it to study the role of complement in AMD as well as develop a gene therapy. Upon completion of these studies, we will have a better understanding of the role of complement in AMD as well as proof of principle for a gene therapy. All this information is necessary before preclinical safety testing and product development for an AMD therapy in humans can take place.

Genetic studies have recently uncovered several genes that can elevate the risk of developing Alzheimer’s disease (AD), including the BIN1 gene as the second strongest genetic risk factor for late onset AD. My lab has generated a BIN1 transgenic model to mimic the increase of BIN1 protein in the brains of people with AD. My goal is to use this transgenic mouse model to investigate how BIN1 functions as a risk factor in AD. I expect that my proposed research will significantly advance the knowledge about BIN1's function in the physiology of the brain, and reveal how it contributes to AD pathology.

Age-related macular degeneration (AMD) is the most common cause of legal blindness in the elderly in developed countries, and is a leading cause of blindness worldwide. The typical American diet is low in nutritional factors that may reduce the risk or severity of AMD. The goal of this project is to determine whether being deprived of these nutrients has consequences for the development of AMD, and to determine the mechanisms by which this occurs. Results from these studies will provide direct evidence for the importance of these nutritional factors in maintaining retinal health and preventing advanced retinal disease, and may reveal new options for therapeutic intervention.

ID:

M2017073

Collaborators:

Paul S. Bernstein, MD, PhD; Martha Neuringer, PhD

July 1, 2017 to June 30, 2019

Macular Degeneration

Standard

$160,000

Recipient of The Carolyn K. McGillvray Award for Macular Degeneration Research

My research aims to determine whether depletion of TAR DNA-binding protein 43 (TDP-43) in neurons contributes to pathological conversion of tau or accelerates tauopathy, a critical driver of neuron loss and cognitive decline in sporadic Alzheimer’s disease (AD). The pathological alteration and aggregation of tau protein (called tauopathy) is arguably the most important alteration in AD, as it shows the strongest association with the loss of brain cells and memory. Many studies have shown TDP-43 abnormality in 30-70% of AD cases, and that these cases show worsened memory loss. The aim of our study is to find out if TDP-43 loss plays a role in the initiation or acceleration of tauopathy in AD. Once we know what drives the changes in tau, we can halt or slow the progression of this disease.

Brain cells are made up of many different proteins that help them work correctly. Bad proteins can build up in the brain cells and cause them to become sick and die in Alzheimer’s disease. We want to study how a group of proteins known as ribonucleic acid (RNA) processing factors may cause bad proteins to build up in the cells. Results from the study may show us a new way to slow or stop the brain cell injury in Alzheimer’s disease (AD).